Preparation of a fluorous chiral BINAP and application to an asymmetric Heck reaction

Article abstract of DOI:10.1016/S0040-4039(02)00407-0

Fluorous chiral BINAP ((R)-F₁₃BINAP) was prepared and was applied to an asymmetric Heck reaction. The enantioselectivity was similar in BTF homogeneous system (90% ee) to that of the original non-fluorous reaction and marginally higher in benzene and FC-72 biphasic system (93% ee) than that of the original non-fluorous one.

Full text of DOI:10.1016/S0040-4039(02)00407-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3053–3056
Preparation of a fluorous chiral BINAP and application to an
asymmetric Heck reaction
Yutaka Nakamura,* Seiji Takeuchi,* Songlin Zhang, Kazuo Okumura and Yoshiaki Ohgo
Niigata College of Pharmacy, 5-13-2 Kamishin’ei cho, Niigata 950-2081, Japan
Received 15 January 2002; revised 21 February 2002; accepted 22 February 2002
Abstract—Fluorous chiral BINAP ((R)-F13BINAP) was prepared and was applied to an asymmetric Heck reaction. The
enantioselectivity was similar in BTF homogeneous system (90% ee) to that of the original non-fluorous reaction and marginally
higher in benzene and FC-72 biphasic system (93% ee) than that of the original non-fluorous one. © 2002 Elsevier Science Ltd.
All rights reserved.
Chiral BINOL and BINAP are among the most useful
and popular ligands for catalytic asymmetric reactions.1
Several kinds of fluorous chiral BINOLs have been
prepared and used as the ligands for catalytic asymmet-
ric reactions.2 If the molecules have enough fluorine
content in the fluorous tags, the ‘fluorous’ molecules are
recyclable in an organic-fluorous biphasic system and
can be recovered easily by organic-fluorous biphasic
extraction (liquid–liquid extraction) or by fluorous
reverse-phase silica gel separation (solid–liquid extrac-
tion) for reuse.3
ruthenium complex catalyzed the asymmetric hydro-
genation of dimethyl itaconate in excellent enantioselec-
tivity (95.7% ee), which is similar to that obtained in
the original Ru–BINAP complex reaction (95.4% ee).
We have recently prepared a more heavily fluorinated
chiral BINAP (F13BINAP) and we report herein the
synthesis of the reagent and its use in a Heck reaction
(Scheme 1).
When the bistriflate of (R)-F13BINOL (II) was phosphi-
nated with Ph2PH by using NiCl2(dppe) in benzotrifl-
uoride (BTF) at 100°C for 3 days under argon, the
desired product (III) was actually seen by TLC analysis
in good yield. However, (R)-F13BINOL and the start-
ing material, bistriflate (II), had very close Rf values on
TLC and it was very hard to separate them by flash
column chromatography. During the workup and
repeated attempts to purify the product with flash
column chromatography, a significant amount of the
desired product was oxidized to the corresponding
dioxide ((R)-F13BINAPO (IV)). Therefore, the crude
product was oxidized with H2O2, and the oxidized
product was easily purified by flash chromatography
and recrystallization (87% yield based on II). That
(R)-F13BINAP (III) is very sensitive to oxygen in the
air and is easily oxidized to (R)-F13BINAPO apparently
stems from its fluorous characteristics. It is well known
that a long fluorous chain has strong affinity for oxy-
gen.6 Next, we examined reduction of (R)-F13BINAPO
by the silane reduction method,7 which has been used
as the standard reduction method of a chiral phosphine
oxide such as BINAP oxide. However, (R)-F13BINAP
was not obtained by the reaction despite close scrutiny
of the reaction conditions. We also attempted to carry
out the reduction by using SmI2–HMPA in the THF
For example, the fluorous BINOLs, F13BINOL and
F17BINOL that we have prepared were sufficiently
fluorous to carry out the catalytic asymmetric addition
of Et2Zn to aldehydes in an organic/FC-72 (FC-
72:CF3(CF2)4CF3) biphasic system and to be recovered
with fluorous reverse-phase silica gel.2a
The important chiral ligand BINAP is usually prepared
from the corresponding O,O%-bistriflate derivative of
BINOL.4 Very recently, Stuart and co-workers reported
the
preparation
of
(R)-6,6%-bis(1H,1H,2H,2H-
perfluoro-1-octyl)-2,2%-bis(diphenylphosphino)-1,1%-
binaphthyl and its application to asymmetric
hydrogenation.5 The ligand was prepared by the con-
ventional procedure from the corresponding BINOL
bistriflate precursor in good yield (85%). The derived
Keywords: Heck reaction; asymmetric reactions; fluorine and com-
pounds; perfluoroalkyl compounds.
* Corresponding authors. Tel.: +81-25-268-1247; fax: +81-
25-268-1230; e-mail: nakamura@niigata-pharm.ac.jp; takeuchi@
niigata-pharm.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00407-0

3054
Y. Nakamura et al. / Tetrahedron Letters 43 (2002) 3053–3056
Scheme 1.
system,8 but the yield was not high and it was practi-
cally impossible to separate (R)-F13BINAP from the
nonpolar by-products. Fortunately, we succeeded in
obtaining high yields of (R)-F13BINAP by employing
Imamoto’s method for reduction of chiral phosphine
oxides.9 The reaction was carried out as follows: (R)-
F13BINAPO was dissolved in DME and then MeOTf
was added to the solution. The reaction mixture was
stirred for 3 h at room temperature under argon. After
cooling to 0°C, LiAlH4 was added to the solution and
then the reaction mixture was stirred at room tempera-
ture overnight. The color of the reaction mixture
changed from light yellow to dark-red and then to
yellow. After, the reaction was quenched by a small
amount of a saturated Na2SO4 solution and then the
reaction mixture was directly loaded on a short silica
gel column and eluted by degassed solvent (hexane/
Et2O=20/1) under argon. Careful workup, purification
and solvent removal followed by flash column chro-
matography under argon afforded an oily residue which
gradually transformed to white crystals (68%).
The 31P NMR spectra of (R)-F13BINAP and (R)-
F13BINAPO showed singlets at −14.1 and 28.7 ppm,
respectively.10 The enantiomeric purity of (R)- and
(S)-F13BINAPO was analyzed by HPLC by using
DAICEL CHIRALCEL OD-H column to be higher
than 99% ee.11 Partition coefficients of (R)-F13BINAPO
and (R)-F13BINAP are shown in Table 1.
In order to get preliminary information about (R)-
F13BINAP, we examined an asymmetric Heck reaction.
Hayashi and co-workers have reported that Pd(OAc)2–
(R)-BINAP catalyzes the reaction between 2,3-dihydro-
furan and 4-chlorophenyl triflate at 40°C for 22 h to
give 2-(4-chlorophenyl)-2,3-dihydrofuran in 91% ee.12
Table 1. Partition coefficients of (R)-F13BINAPO and (R)-F13BINAP in organic solvent and FC-72
F (%)
53.09
53.70
Method
Organic solvent
FC-72/organic solvent
(R)-F13BINAPO
(R)-F13BINAP
A
A
A
B
B
B
CH2Cl2
Benzene
Benzene
Benzene
CH3CN
DMF
76/24
90/10
79/21
74/26
98/2
98/2
Method A: A mixture of 100 mg of (R)-F13BINAPO or (R)-F13BINAP in FC-72 (2 mL) and organic solvent (2 mL) was stirred at room
temperature for 10 min. Then the two phases were separated and the solvents were evaporated in vacuo. The contents of the fluorous compound
in each phase were determined by weighing the residue.
Method B: A mixture of 20 mg of (R)-F13BINAP in purified FC-72 (1 mL) and organic solvent (1 mL) was stirred at room temperature for 10
min under argon. The contents of the fluorous compound in each phase were determined by HPLC analysis.

Y. Nakamura et al. / Tetrahedron Letters 43 (2002) 3053–3056
3055
Table 2. Asymmetric Heck reaction of 2,3-dihydrofuran with 4-chlorophenyl triflatea
Entry
Ligand
Solvent
Reaction time (h)
Yield (%)b
1/2
% eec (config.)d
1
2
1
2
1
2
3
(R)-BINAP
BTF
BTF
24
77
62
62
50
67
59
59f
39
2f
6
8
92/8
76 (R)
90 (R)
92 (R)
93 (R)
93 (R)
NDe
NDe
NDe
NDe
NDe
(R)-F13BINAP
(R)-F13BINAP
(R)-F13BINAP
(R)-F13BINAP
88/12
72/28f
69/31
62/38f
Benzene
Benzene–FC-72 (1:1 v/v)
Benzene–FC-72 (1:1 v/v)
22f
18
4
5g
B1f
a 4-Cl-C6H4OTf:2,3-dihydrofuran:i-Pr2NEt:Pd(OAc)2:ligand=1.0:5.0:3.0:0.03:0.06 (molar ratio).
b Isolated yield.
c Determined by capillary GC analysis using SUPELCO b-DEX 120.
d Assigned by the sign of the optical rotation.
e Not determined.
f Determined by capillary GC analysis with SUPELCO b-DEX 120 by using mesitylene as an internal standard.
g The fluorous phase in entry 4 was reused as the catalyst solution.
F13BINAP had good solubility in fluorinated solvents
and provided similar enantioselectivity in the BTF
homogeneous system to that of the original reaction
and higher enantiomeric excess in the benzene/FC-72
biphasic system than that of the original one. However,
(R)-F13BINAP is easily oxidized by a trace amount of
oxygen in the fluorous phase during the reaction,14
probably because of the strong affinity of the fluorous
solvent and the tags of (R)-F13BINAP for oxygen.
Therefore, preventing (R)-F13BINAP from oxidation
throughout the reaction is the main problem to be
solved to achieve more success.
We carried out reactions under the same reaction con-
ditions except that BTF and (R)-F13BINAP were used
as the solvent and the chiral ligand,13 and the results
are summarized in Table 2 (entries 1–3). As seen in
Table 2, the reaction rate is lower in the case of
(R)-F13BINAP than in that of (R)-BINAP. BTF is a
good solvent for (R)-F13BINAP (entry 2, 90% ee) but
not for (R)-BINAP (entry 1, 76% ee). Benzene was also
a good solvent for (R)-F13BINAP (entry 3, 92% ee),
although the chemical yield of 2 increased. The enan-
tiomeric excess of product 1 was determined by GC
analysis using a SUPELCO b-DEX120 chiral capillary
column. (R)-F13BINAP was recovered by using
fluorous reverse-phase silica gel3a,b,h in about 70% yield.
However, this percentage of recovery was not precise
because the recovered material was a mixture of (R)-
F13BINAP and (R)-F13BINAPO (mostly (R)-
F13BINAPO).
Acknowledgements
The authors would like to thank Professor Dennis P.
Curran, University of Pittsburgh, for his helpful sugges-
tions and Professor Yasuhiro Kajihara, Yokohama
National University, for the measurement of 31P NMR
spectra of (R)-F13BINAP and (R)-F13BINAPO. They
also wish to express their thanks to the Laboratory for
Organic Elemental Microanalysis, Faculty of Pharma-
ceutical Sciences, Kyoto University, for the elemental
analysis of (R)-F13BINAPO. This work was partially
supported by Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports and Culture,
Japan.
Finally, we carried out the Heck reaction in a benzene/
FC-72 biphasic system (entries 4 and 5 in Table 2). The
enantioselectivity was marginally higher (93% ee),
although the chemical yield was much lower (39%) than
in the original reaction (entry 4). After the first reac-
tion, the benzene layer was changed for a fresh sub-
strate benzene solution to test for recycling of the
catalyst. However, the reaction did not proceed at all,
probably because of inactivation of the catalyst by
ligand oxidation (entry 5). (R)-F13BINAP was demon-
strated to have been oxidized in the FC-72 phase by
monitoring with TLC. The color change of the FC-72
phase from wine-red to brown midway in the first
reaction suggested the inactivation of the catalyst also.
References
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In conclusion, we have prepared a fluorous BINAP,
(R)-F13BINAP, and examined an asymmetric Heck
reaction. The preliminary results revealed that (R)-

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Y. Nakamura et al. / Tetrahedron Letters 43 (2002) 3053–3056
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11. The optical purity was determined by HPLC analysis
using chiral column (DAICEL CHIRALCEL OD-H,
hexane:2-propanol=100:1, flow rate=0.5 mL/min): tR=
10.8 min for the (R)-enantiomer and tR=15.2 min for the
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Chlorophenyl trifrate (160.8 mg, 0.617 mmol), (i-Pr)2NEt
(252 mg, 1.95 mmol) and 2,3-dihydrofuran (230 mg, 3.28
mmol) were added to a solution of (R)-F13BINAP (116
mg, 0.042 mmol) and Pd(OAc)2 (4.2 mg, 0.0187 mmol) in
BTF (2.2 mL) and the solution was stirred at 40°C for 77
h under argon. The reaction mixture was diluted with
Et2O (30 mL) and washed with water (10 mL) and brine
(10 mL). The organic layer was dried over anhydrous
MgSO4 and concentrated in vacuo. The residue was
dissolved in Et2O (2 mL). ((1H,1H,2H,2H)-perfluoro-
octyl)dimethylsilyl bound silica gel (1 g) was added to the
solution, and then the solvent was evaporated to dryness.
The powder obtained was loaded on a column of
((1H,1H,2H,2H)-perfluorooctyl)dimethylsilyl bound sil-
ica gel (3 g) and then eluted successively with acetonitrile
(15 mL) and FC-72 (40 mL). The acetonitrile fraction
was evaporated in vacuo and purified by silica gel column
chromatography (pentane:Et2O=20:1) to give (R)-1 (66
mg, 59% yield) in 90% ee and 2 (9 mg, 8%). GC analysis
using SUPELCO b-DEX chiral capillary column: (He=
1.0 mL/min, DET=250°C, INJ=240°C, OVEN=110°C
(1 min) to 170°C, 2°C/min, Split=100:1): tR=28.1 min
for (S)-1 and tR=28.4 min for (R)-1. A (R)-F13BINAP
and (R)-F13BINAPO mixture was obtained from the
FC-72 fraction (86 mg).
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10. (R)-F13BINAPO: White powder from hexane, mp 164–
20
578
166°C; [h]2D0 +94.6 (c 1.02, BTF), [h]
+99.2 (c 1.02,
20
546
20
BTF), [h] +113.8 (c 1.016, BTF), [h] +206.6 (c 1.016,
436
+333.9 (c 1.016, BTF); 1H NMR (CDCl3)
20
BTF), [h]
365
l
1.10–1.18 (m, 6H, –CH2C–), 1.95–2.11 (m, 6H,
–CF2CH2–), 6.79 (d, 2H, Ar–H, J=8.4 Hz), 6.89 (d, 2H,
Ar–H, J=8.4 Hz), 7.19–7.72 (m, 22H, Ar–H), 7.91 (dd,
2H, Ar–H, J=2.0 and 8.7 Hz), 7.94 (s, 2H, Ar–H); 31P
NMR (CDCl3): l 28.7; anal. calcd for C92H54F78O2P2Si2:
C, 39.59; H, 1.95. Found: C, 39.45; H, 1.89.
14. Since no efficient method has been reported for removing
oxygen from FC-72 and BTF, we just degassed under
reduced pressure or bubbling argon gas into the solvents
just before use. Therefore, the solvents might contain a
trace amount of oxygen. Oxygen in the air could also
enter the reaction vessel through the serum cap during
the reaction.
(R)-F13BINAP: 1H NMR (CDCl3) l 1.08–1.18 (m, 6H,
–CH2C–), 1.95–2.11 (m, 6H, –CF2CH2–), 6.79 (d, 2H,